Wednesday, March 28, 2012

The results of the IMMEDIATE trial have been popping up repeatedly today on Facebook, partly because I "like" a few EMS FB pages, and also because one of the authors (Hi Carin!) is a FB friend and recent Yale ED attending.

Here's an example of the way the trial is being described:

"ACS patients benefit;" "cut the risk of death in half." Sounds great! I love medical reporting/press releases. No pesky nuance or qualification. Me no need anyhow.

The result they are describing, to be specific, is that 8.7% of the people getting the placebo had a cardiac arrest, or died while they were hospitalized, while only 4.4% of the patients getting the study drug did. That's either an (absolute) difference of 4.3%, or about a (relative) 50% decline.

Such an effect would be stunning. In the years after thrombolytics and aspirin were introduced, the incremental benefits of new therapies for AMI have been getting smaller and smaller. This result here would blow the others out of the water.

For instance, back in 1988, it was shown in ISIS-2 that either the use of aspirin or of thrombolyticsreduced the risk of deathin MI by about 2-3% over placebo. The combination was better of course.

After that, it's been harder to show that the more complicated and expensive therapies save that many more lives. When we send a patient to the cath lab for an AMI (instead of giving a thrombolytic in the ED), for example, there isn't that huge a benefit. One recent analysis suggested that, overall, you could only find a 0.7% difference in mortality (6.6% vs 5.9%) between lysed patients, and those that went for PCI. A lot of money for not much gain.

So, if this combination of glucose, insulin, and potassium (GIK) could cut mortality in AMI from 6.6% to, say, 3.3%, it would be freakin' amazing.

"I bet there's a catch. There's always a catch."

Well, I don't mean to be an Eeyore, but the perhaps we should wait for, yes, "further study." I offer three reasons why:

1. They weren't studying mortality.

The principle outcome they were studying was whether the initial presentation of ACS would progress to an MI, or it would be an "aborted" MI. This is the outcome that they believed had the most biochemical and clinical justification, and they clearly thought that it had a reasonable chance of being demonstrated.

It turns out there was no difference in the percent of people who progressed to completed MI - the GIK infusion did not help, at least not here. So the trial is negative for the real primary outcome.

2. There were 12 secondary outcomes.

Look at the table of the results:

Remember: the outcome they staked the success of the trial on was the one at the top: "Progression to MI," for all participants. The rest are a bunch of secondary outcomes, and they don't count to the same degree as the primary outcome.

Analogy: A friend is flipping a coin, and you call heads. That's your primary outcome of interest. But if you also say to your friend "Okay, I call heads, but I also call it if you drop the coin, if it flips over 5 times in the air, if your phone rings in the next 30 seconds, or if your nose starts to itch in the next 10 seconds.

Now, you may be wrong about heads, but say your friend's nose does indeed start to itch in the next 10 seconds? Will he concede defeat? What will he say?

"No pick! NO PICK!"

Most likely your friend will point out that the most relevant and important prediction you made was heads vs tails. Furthermore, you called out such a long list of other items that you were almost certain to come up with a positive result. He will insistent on another coin toss, where the primary outcome is now nose-itching, not heads or tails.

The same holds in statistics and study design, and is also why the authors state in their conclusion (my emphasis):

"The primary end point was not significantly different between groups, and the observed favorable results of GIK were based on prespecified but secondary end points, although biologically plausible and consistent with preclinical studies. The study tested one primary hypothesis, 3 major secondary, and 6 other secondary hypotheses. All were prespecified and no adjustment for multiple comparisons among the secondary end points was made; thus, reported significance levels should be considered approximate. Accordingly, given the lack of complete consistency of the findings, and the modest P values for most of the statistically significant findings, it would be appropriate to describe the observed favorable effects on the secondary outcomes as generating clinically testable hypotheses for evaluation in larger cohorts."

3. 30 day mortality seems pretty important too...

Ok, say you can take the "cardiac arrest or in-hospital mortality" results at face value. What, then, shall we make of the 30-day mortality? It was shown to be basically the same in both groups.

We just saw this discussion take place last month. A study from Japan showed that giving epinephrine in cardiac arrest got people to the hospital with ROSC more often, but the 30-day mortality was no different (We'll leave the neuro results alone for now.).

It would be nice if epi put all the dots on the right side of the graph. But it doesn't.

So, say the results are right - people don't die or arrest in the hospital as often, but they still die in the first 30 days just as often. Now, maybe everyone's hospital stay was over 30 days, but I doubt it.

Still feel excited?

Bottom line:

If they conduct another study that confirms the mortality benefit, it would be the greatest thing since the free coffee machine in the ED break room. But, unlike the coffee machine, such results are conjecture for now.

Tuesday, March 20, 2012

Meir and I were talking during a recent shift, and he asked the perceptive question "What's the deal with giving dextrose in a cardiac arrest?"

Good question!

You know that there's a lot of controversy about how to run a cardiac arrest - intubating or not, how often to ventilate, or doing a short trial of CPR before defibrillation. This is especially true regarding the "code drugs," like epinephrine.

Well, okay. Epi works.

But at least when it comes to epinephrine and amiodarone, there are some studies out there, some base of evidence to start the discussion from. This is not true for D50.

If you look in the 2000 ACLS guidelines, you'll see the list of the "reversible causes" of cardiac arrest. It doesn't include hypoglycemia.

If you don't believe me, look at the fine print at the bottom.

Now skip ahead 5 years, and we now see that hypoglycemia has been added (2005 ACLS):

Down in the green box, at the bottom.

Read through the guidelines, though, and you'll see that not a word is uttered about why this was added.

Now, fast-forward to 2010, and they've taken it out! And, just like they added it without comment, it's gone without justification or evidence, nor even a mere "clinical evidence suggests."

Poof!

Since the AHA elected not to review any relevant evidence about the topic, I decided to answer some questions about hypoglycemia, cardiac arrest, and the relative benefit of trying to squeeze that huge syringe of syrup into an IO.

1. Does hypoglycemia cause cardiac arrest?

You figure this would be easy enough to answer, but there is almost no direct data that suggests hypoglycemia is a cause of cardiac arrest, let alone a treatable cause.

One case series in 1995 reviewed 3 arrests that the authors thought were associated with hypoglycemia. These patients all had significant primary problems (active CAD, cerebral hemorrhage, and severe pancreatitis), so it's hard to assign blame to the blood sugar.

Another case series, looking at patients with severe heart failure, concluded that one cardiac arrest was due to hypoglycemia (oddly enough, she didn't have diabetes). And in one last example, a patient in the ICU became asystolic at the same time her blood sugar was plummeting, although she also was developing a severe hyperkalemia at the same time.

The problem with this handful of case reports is that, given the uncontrolled nature of the situations, it's hard to point out cause and effect. Just because one thing occurred at the same time as something else, or even right after, doesn't mean they're related.

Well, look at this from a different point of view. Is there a proposed "mechanism," some physiological theory, that suggests that hypoglycemia could cause an arrest?

There is the phenomenon of the "dead in bed" syndrome, where a relatively healthy diabetic is found deceased in the morning. A number of researchers think they've found a link - the usual dip in blood sugar levels at night can cause a prolongation of the QT interval. And long QT intervals can sometimes cause problems! (See these examples at Dr. Smith's ECG Blog.)

They've been able to show this effect both in the lab (giving insulin to healthy people) and at home (people on continuous ECG and glucose monitoring).

But, just because you can show a longer QT, doesn't mean you have a smoking gun! Others have pointed out that there are probably a number of other factors involved. For instance, it may not be the hypoglycemia that triggers the QT changes, but in fact may be the body's own epinephrine that kicks off the arrythmias!

Now epinephrine is bad for the heart?!?

So, we just don't know.

2. Is the finger stick accurate in cardiac arrest?

Usually, the capillary blood glucose is pretty close to the venous level, close enough that we all trust it. However, in the critically ill patient, the capillary level becomes less accurate, as a number of studies have shown.

Only one study has looked at patients getting CPR, though. This was a pretty big study by cardiac arrest standards - they checked the venous and capillary glucose levels in 50 cardiac arrest patient. It wasn't encouraging.

There were 4 patients with "true" hypoglycemia, found on the venous samples sent to the lab. The fingerstick missed 1 of those, and also managed to misdiagnose 5 patients as having hypoglycemia, when they really didn't. (That works out to 75% sensitive, and 38% specific).

Not so useful. So, perhaps we should just skip testing, and treat empirically. What could be the harm in that?

3. What's the harm in empirically treating for hypoglycemia?

Glad you asked.

It's the same reason we're trying to cool people down after we get a pulse back - neurologic outcomes. In some studies, they gave dextrose to some cats before they put 'em into cardiac arrest, while other cats they didn't. The cats who didn't get sugar beforehand had better brains afterwards.

You can't really do this same kind of study in humans (for example). One group in Helsinki, though, checked the blood sugar on VF cardiac arrests, and looked at how well they recovered. Patients who had increases in their glucose after resuscitation didn't survive to hospital discharge as often. This is just the latest evidence - see this review article (50% dextrose: antidote or toxin?) for plenty of other examples.

4. Any evidence giving sugar helps?

Well, yes and no. There is no evidence that pumping liquid rock candy into someone's tibia helps in cardiac arrest.

Medicine!

Now, there are a lot of other sick people out there, people teetering on the edge, critically ill, septic, metabolically deranged - with a blood sugar headed south, and fast. You have to find those folks and treat them quick. Some of these are kids, with weird metabolic problems, or with sepsis. But the key is to get to them before they crash, while they still have a pulse.

The authors of the only review I found on this topic concluded that (my emphasis):

"This is obviously a controversial issue and raises the point of whether we should still be teaching that hypoglycaemia is a reversible cause of cardiac arrest when there seems to be not enough evidence to support this.

Current evidence would suggest that patients may suffer cardio-respiratory arrest with hypoglycaemia, but not because of it."

The Bottom Line

Despite the huge crowd in the room whenever a patient is "coding," there are only a limited number of spaces around the patient. Likewise, you have the contents of the whole code cart available to you, but can only push each drug one at a time. You have to pick your priorities in a code, and it doesn't appear as though pushing sugar water ought to one of those.

Saturday, March 17, 2012

I recently gave procainamide to a patient in the ED. It was a big fuss - we had to send a runner to the pharmacy, the nurse had to blow the dust off the administration protocol. Great fun.

Later on I was describing this to another ED attending, and one of the senior trauma surgeons, overhearing this, exclaimed "You're not old enough to give procainamide!"

He proceded to launch into an Abraham Simpson-esque tale about long-lost antiarrhythmics, and I sort of lost the point of his story...

"... which was the style at the time...

Anyway. The point today is that procainamide is back, and we should be thinking of giving it far more often than we do.

For example, with...

Stable monomorphic ventricular tachycardia

Yet another "chest pressure and palpitations gets rolled into major med. He looks good, no acute distress, joking awkwardly with the techs as the monitor leads are attached. You dutifully punch in the orders for a chest x-ray, troponin, etc., when you notice this on the monitor.

"Is he just shaking real bad?"

Ah. Well, it turns out that his vitals are just fine, and he looks stable enough, but you could use "synchronized cardioversion" to fill out your procedure log. Unfortunately, he just ate a couple burritos on the way over. That's going to make procedural sedation a little dicier, so perhaps you'll try a medication. But which one?

On the one hand, there's amiodarone, which seems reasonable, given how often it's given in the ED. On the other hand, lidocaine is readily at hand.

Dose: Give 1 box.

Well, the AHA thinks that procainamide is likely your best bet here. Just sayin'.

If it's not, the evidence is best (level B) that procainamide converts VT more often than anything else. In one trial procainamide terminated 38/48 episodes of VT - not as good as electricity, but pretty good!

They do recommend amiodarone for the patient who is unstable and has failed cardioversion, and in whom the other drugs aren't working either. One reference that the guidelines cite in support of using amiodarone describes evidence that "demonstrated a dose-response relation, with at least comparable efficacy to bretylium."

You got a 40 year old guy in the ED, who says that he started having strong palpitations about 2 hours ago while at work. No recent drinking, no drugs, but he does quite a bit of running, however.

A healthy patient with a clearly defined time of onset - a great candidate for ED cardioversion! You get the pads, set up the airway gear, and calculate the propofol dose. As you consent him, however, you learn that 30 minutes ago he wolfed down one of these:

Crumb. That's not going to look so great going down his right mainstem. Well, how about drugs?

Well, amiodarone seems to be the default choice. The 2006 AHA guidelines seemed pretty bullish on amio, giving it a Class IIa rating for conversion of AF, relegating procainamide to a measly Class IIb. The funny thing is, their summary of the utility of amio in AF is not exactly inspiring. They describe trials of amiodarone that show it to be "no more effective than placebo," and "more effective than placebo after 6 to 8 h and at 24 h but not at 1 to 2 h."

They relegate procainamide to the list of drug that are "Less Effective or Incompletely Studied," which has to reflect a little anti-north-of-the-border bias, given that the Canadian cardiologists had already looked over the world's literature, and come to a different conclusion.

When Canadians want to convert AF in the ED, they reach for procainamide. In the 2010 Canadian Cardiovascular Society Atrial Fibrillation Guidelines (also here as a PDF download), our Canadian brethren ranked the best drugs for conversion of recent-onset AF:

"Amio has to be here somewhere..."

One trial was used to cite the effectiveness of procainamide in AF (happened to be a Canadian paper, but published in a U.S. EM journal), showing that it converted about half of the patients. They don't cite other papers, but past results (from 1983 and 1993, for example) could also be used to support the guidelines. One recent trial (done by the same Canadian) showed a 60% cardioversion rate.

Canadian cardiologist, showing their pride with a tattoo on their... Ok, what body part is that?

Wide complex atrial fibrillation, possible WPW.

So, by this point, you're a wiz at terminating VT, you've mastered the art of atrial fibrillation - there is nothing can triage can do to hurt you.

Fifteen minutes before the end of your shift, they roll in a middle-age women with "palpitations." No problem for a boss like you - you'll have major med tidied up for sign-out in no time.

"Challange Accep... Geez, is that her ECG?"

The tech hands you this ECG:

Her blood pressure is fine, and she doesn't look too symptomatic. She tells you that she has some "extra wires" in her heart, and that she gets spells like this sometimes.

Sooo, irregular wide-complex tachycardia. This could be WPW with atrial fibrillation, so your therapeutic options just narrowed. No metoprolol, no diltiazem. Again, it would be great to cardiovert her, but she doesn't want to consent for that.

So it was not a suprise when the AHA updated the atrial fibrillation guidelines last year, and bumped procainamide up to a Class I recommendation for AF in WPW. Amiodarone is still okay to use, but it is class IIb - weak!

Bottom line

Brush up on your dosing, cuz' this drug is back like horned rim glasses - so old fashioned that it's back in style.

Sunday, March 11, 2012

A recent study got a bit of press, and it got me to thinkin'. Specifically, it got me to thinking about those clinicians who say stuff like "Women typically present atypically," and stuff like that. Like they're a whole other species when it comes to matters of the heart.

Now, I was going to go through the results, look at the past literature, put things in context... Boring! The heck with that - I'm going in a different direction.

I figure that if women are so different from men when it comes to ACS, then they must have different symptoms with a bunch of other diseases as well. Right? So here goes!

Pancreatitis
Why don't we talk about how men and women present differently with pancreatitis? Both the heart and the pancreas are visceral organs, with indirect transmission of nociception, and are subject to hormonal influence. Although there is a clear divide in etiology based on gender (men drink, women get gallstones), there doesn't appear to be any difference in the symptoms.

Extensive Pubmed and Google searches turned up only one somewhat relevant paper. Unfortunately, they only studied the relationship of patient gender to disease severity, and made no comments about symptoms at presentation.

Bottom line: Absolutely no data in the literature, on way or another. Anybody need a research project?

Pulmonary embolism
So, just like MI, this is a bad one to miss. Just like the heart, the symptoms can be protean and vague, and hormones like estrogen are often implicated. Should be a slam-dunk for a difference in symptoms!

Swiss researchers combined the results of 3 prospective trials, looking at the clinical presentation of 3414 outpatients with suspected PE. When they looked at the all the data, they found that, apparently, women and men presented with about the same symptoms (small exception - men more often had a concomitant symptomatic DVT). Warning - big slug of data here:

Note that men and women both had chest pain at about the same rate - very reassuring! There are some small differences, but aside from DVT symptoms, nothing is statistically significant. In addition, both the Wells and Geneva scores showed comparable performance in both genders.

Bottom line: It's only one paper, but it has a great design.

Stroke
Along with STEMIs and major trauma, stroke is one of the big three time-dependent, resource-intensive, emergency medicine priorities. Now, given that the history and physical exam are so crucial in our evaluation of tPA candidates, it would be good to know if we had to adjust our diagnosis to the gender of the patient. There have been 3 recent studies, with different methods, that all speak to this issue.

Lisabeth 2009 used interviews, asking the patient what symptoms had brought them to the hospital. These interviews were conducted after admission, but despite the potential for recall bias, few differences were found: Only "mental status change" rose to (marginal) significance.

Gargano 2009 was also performed in Michigan, but used registry data from almost two thousand admissions. Instead of interviewers, they abstracted data from ED documentation.

There appear to be few significant differences between the sexes here. Men having slightly more "balance/dizziness" problems than women, which seemed to drive the marginal difference in "Any warning sign or suspect stroke." Even the authors concede that:

"Overall, the sex differences in symptoms we identified were relatively minor..."

Women were significantly less likely to have dysarthria, ataxia, or paresthesia at stroke onset than men, but more often had incontinence, loss of consciousness, visual deficits, and dysphasia. ... Despite sex differences in the prevalence of signs and symptoms, the ranking of the top 5 symptoms was similar for men and women.

Bottom line: Minor differences, of little clinical significance across a number of sites and study designs. Here, at least, men act like women. Or the other way around.

Appendicitis
No only is the hormonal milieu different in this case, but the anatomy as well! With all the added adnexa & "stuff," the differential diagnosis is expanded, and the evaluation, and especially imaging choices, can be quite different for the boys and the girls.

And cylons. Cylons definitely have atypical presentations.

So it's reasonable to think that the presenting symptoms would be significantly different as well. I only found 2 studies that fit the bill, however, and they have some disappointing shortcomings.

Guss 2000 looked at 196 ED patients who ended up with a diagnosis of appendicitis. Now this is the funny thing - the women had longer diagnostic work-ups before operation, but the men had higher rates of perforation. Apparently, though, they presented in much the same manner:

Oddly, there is no mention of RLQ tenderness here. Although the methods described how tenderness at McBurney's point was to be included, no mention is made in the results. Strange omission...

A similar study was done by McGann-Donlan 2009, comparing 137 men and women, by chart review, who had received a diagnosis of appendicitis. Rather than a surgical diagnosis, the CT scan was taken to be the "gold standard" of diagnosis. (By contrast, only 3 patients in Guss 2000 had CTs!)

Hmm, shouldn't there be some p's kicking around? Perhaps a SD or two, or even, heaven forfend, some confidence interval? Ah, no. Let me quote (italics from the original):

Females more commonly had nausea (66% of females vs 43% of males), vomiting (37% of females vs 32% of males), and diarrhea (18% of females vs 7% of males). Females less commonly had RLQ (right lower quadrant) pain (77% of females vs 88% of males) and fever (1.5% of females vs 7% of males). There was nodifference in anorexia between genders (29% of females vs 30% of males)

Apparently italics are the new p-value. Brady, did you already know this?

Now, the problem with these two studies is that they only looked at patients with diagnosed appendicitis - they didn't look at patients with suspected appendicitis.

Eskelinen 1994 took a whole other approach. They collected data prospectively from over a thousand patients presenting with abdominal pain (not just those with confirmed appys), and tried to construct gender-specific prediction models (unlike, e.g., the MANTRELS score). Through multivariate analysis they determined the independent predictive elements for men and women. The elements in the "B" column are the regression coefficients - the higher the number, the higher the weight that element contributes to the score. Comparing men % women, we find:

Well, it looks like RLQ pain is the most important element for both genders. Most of the other symptoms washed out of both models - migration, intensity, anorexia, etc.

Bottom line - There appears to be no consistent, clinically significant difference between the genders in appendicitis.

Lyme
On one hand, you wouldn't expect Borrelia to show up differently in men & women, since it's a freakin' bacteria. What does it know?

That's how B. burdorferi rolls.

On the other hand, this disease was first diagnosed in CT after one mother insisted that her child's disease that was being misdiagnosed. Since that dynamic (i.e. doctor vs lay-woman) is part & parcel of the Lyme disease history, you might expect some gender-based analysis in the literature.

First, the lead author is employed at the Lyme Disease Research Foundation, which is an organization founded & run by the last author, Aucott. In other words, the last author is the boss of the first author.

Boss? Time for a gratuitous picture of my hero!

Second. it's kind of a crap paper. All the Lyme symptoms were diagnosed by 1 doctor - Dr. Aucott.

Last, it has an agenda. Many proponents of "chronic Lyme" believe current immunologic techniques of diagnosing Lyme disease do not work. (This notion, by the way, has no support from people who actually did fellowships in ID.) The paper here will likely be used to suggest that such tests discriminate against women, even in early disease. They're using the shield of "gender-based medicine" to advance their chronic Lyme agenda. For example:

Conclusion
Whatever your take on the cardiology literature is, I found little evidence that demonstrated that women evince significantly different symptoms than men in a number of other acute diseases.